The present invention is directed to a method of inhibiting or reducing muscle protein degradation in mammals. More particularly, the invention is directed to a method of reducing the breakdown of muscle protein in human patients recovering from surgery or suffering from a muscle wasting disorder.
Various disorders and conditions are characterized by protein wasting or depletion. Such disorders or conditions are often referred to as "nitrogen wasting" diseases or conditions because the patient's nitrogen balance is negative as a result of protein depletion. Such conditions occur in diseases such as malnutrition, uremia, liver disease, cancer, diabetes, sepsis (chronic infection) as well as resulting from such events as burns, surgery, trauma, etc.
Protein depletion may occur because of an unusually high rate of protein degradation or an unusually low rate of protein synthesis, or a combination of both. Thus, if the rate of protein degradation in the body is normal, but protein synthesis is impaired so that the degraded protein is not replaced by newly synthesized protein, protein depletion will occur. Similarly, where protein synthesis is normal, protein may still be depleted if the rate of protein degradation is unusually high due to some disease or condition. Still further, both the rates of protein synthesis and protein degradation in the body may be abnormally high or low to such an extent that the normal nitrogen balance is disturbed and the net result is protein depletion or nitrogen wasting.
Numerous attempts have been made to control one or both of these mechanisms in various disorders in order to conserve nitrogen and prevent protein depletion. For example, U.S. Pat. Nos. 4,100,160; 4,100,161 and 4,100,293 of Mackenzie Walser and assigned to The Johns Hopkins University disclose various treatments for promoting protein synthesis and conserving protein (nitrogen), particularly in patients suffering from renal and hepatic disorders, by the administration of various combinations of essential amino acids with keto and/or hydroxy analogs of certain of the essential amino acids. In addition, U.S. Pat. No. 4,100,161 describes and claims compositions for promoting protein synthesis and conserving nitrogen in patients on protein-restricted diets using a composition consisting of a mixture of the keto-acid analogs of the branched chain essential amino acids valine, leucine and isoleucine.
U.S. Pat. Nos. 4,228,099 and 4,320,146 of Mackenzie Walser describe the use of ornithine and arginine salts of alpha keto analogs of branched chain essential amino acids, particularly arginine alpha-ketoisocaproate and ornithine alpha-ketoisocaproate for promoting protein synthesis by improving nitrogen balance in the treatment of liver disease. Still further, U.S. Pat. No. 4,296,127 of Mackenzie Walser discloses that mixed salts of essential or semi-essential amino acids and nitrogenfree analogs thereof may be useful in the treatment of nitrogen wasting disorders and protein malnutrition.
More recently, it has been found that branched chain keto acids, particularly the ornithine salts, including a major portion of the alpha-ketoisocaproate and smaller amounts of the keto-analogs of valine and isoleucine, have a significant effect in reducing muscle protein degradation in Duchenne muscular dystrophy, a disease in which the rate of synthesis and degradation of muscle protein are both greatly accelerated. P. M. Stewart et al. "Branched-Chain Keto Acids Reduce Muscle Protein Degradation In Duchenne Muscular Dystrophy", Muscle And Nerve, Pages 197-201 (March 1982). Branched-chain keto acids, especially alpha-ketoisocaproate, have also been found to spare nitrogen (reduce protein wastage) in fasting obese subjects. W. E. Mitch et al., "Nitrogen Sparing Induced By Leucine Compared With That Induced By Its Keto Analog, Alpha-Ketoisocaproate, In Fasting Obese Man", Journal of Clinical Investigation, Volume 67, Pages 553-562 (February 1981). Still further, it has been reported that whereas leucine itself probably stimulates the synthesis of muscle protein in vitro, alpha-ketoisocaproic acid (ketoleucine) in vitro inhibits muscle protein breakdown without stimulating protein synthesis. The latter studies were based on isolated rat diaphragms and atria. M. E. Tischler et al., "Relationship Of Leucine (Leu) Catabolism To Its Regulatory Effects On Protein Turnover In Muscle", Federation Proceedings (Federation of American Societies for Experimental Biology) Vol. 39, Page 1682 (May 1980).
Despite the latter reports of Mitch et al. and Tischler et al., leucine has not been found to reduce muscle protein degradation in vivo, nor has it been found to promote protein synthesis or reduce muscle protein degradation in obese men. Hence, in view of the complete conversion of leucine to ketoleucine in the body, no advantage has been seen to administering ketoleucine in muscle wasting disorders or conditions.